What causes immune decline?
How are CD4s depleted
CD4 & CD8 quantity or quality, what matters?
STIs: response to HIV during an STI

Immunology of the past decade has eclipsed the ability of most patients and their clinicians to readily understand the current theories and debates. The immunology literature is reserved for those who speak the molecular language of the field. Notwithstanding, inside immunology lies an ability to understand and conquer HIV as a human illness. To that end I will attempt to highlight and simplify some of the recent developments in the field of Immunology that were presented through a number of lectures and posters at the 41st ICAAC, December 2001.

Even before the discovery of the HIV virus, it was known that those who were ill with PCP pneumonia or KS lesions suffered from a loss of immunity due to lower cd4+ T-cells. More then 20 years later the mechanisms of how HIV causes this depletion of T-cells is not understood. When someone is initially infected with HIV, CD4+ T-cells decline rapidly. But soon thereafter the CD4+ T-cell numbers rebound while at the same time the amount of HIV virus declines. At this point in HIV infection the immune system has some control over HIV replication. Why then does that control eventually fail?

Theories:

Exhaustion - One of the earlier theories was that a persistently high CD4+ T-cell turnover rate, (70 times normal), exhausted and wore out the systems ability to replenish T-cells. More recent work suggests that while HIV does increase the turnover rate of both CD4's and CD8's, the rate is much more modest, perhaps a 2-3 fold increase.

Hyperactivation - Immune over-activation is a problem in a number of human illnesses. Perhaps the best described is rheumatoid arthritis, where the immune system attacks the bodies own tissues and can lead to joint pain, disfigurement, and disability. Markers on both CD4 and CD8 T-cells that are characteristic of activation have also been associated with HIV disease progression.

Interestingly, HIV-2, where CD4+ T-cells decline slower, and thus AIDS is reached over a longer period of time, is associated with lower levels of immune activation markers. Also in sooty mangabeys (monkeys), animals that naturally harbor the SIV virus, SIV viral loads are high, however CD4+ T-cells do not decline with time and there is no sign of immune activation. These monkeys do not develop AIDS from their infection.

Another clue toward understanding the failure of the immune system after HIV infection:

The human immune system controls HIV replication, to some degree after infection, for a period of years. At the beginning of HIV infection the cells that are predominantly infected are CCR5+ CD4+ T-cells. The virus that infects these cells has been phenotypically called NSI virus (non syncitium inducing virus). NSI received its name during the early days of the epidemic when it was noticed that there could be two distinct histologic manifestations of this disease. One where the infected cells remain discrete and are not clumped together. The NSI virus was contrasted to a second histologic feature noted among AIDS patients where the infected cells seemed to Velcro other cells around it into clumps. The clumped cells were called synctium and were associated with worse prognosis. As the field has developed, we now know that as the HIV infection progresses, the virus' pattern changes from predominantly infecting CCR5+ T-cells (activated memory cells) to infecting CXCR4+ T-cells (both naive and memory cells). Put another way the virus changes with time from an NSI (non syncitium inducing, less pathogenic) virus to an SI (syncitium inducing, more pathogenic) virus. It is currently suggested that this switch in the type of cells infected is important in the ultimate demise of the immune system due to the loss of naive CD4+ T-cells. Naive T-cells are extremely important for a proper immune response to a new infection.

Immune Function (Quality):

The numerical decline in cd4+ T-cells is only the beginning for understanding the immune deficiency that is seen with HIV disease. How CD4 & CD8 T-cells are functioning is also an important area of interest. Function of immune cells can now be measured by a number of techniques (tetramers, Elispot, ICS, viral genome sequencing, proliferation assays) and the most recent findings are perplexing. In contrast to the previous dogma, recent studies suggest that CD8 and CD4 CTL responses to the HIV virus, even in advanced HIV disease, are robust but not necessarily correlated with protection. It has been observed that those patients with the highest viral loads have been shown to have the most robust CD8+ HIV specific CTL responses. Yet having these responses was not protective of HIV replication or immune system damage. This is not to suggest that function is not important. We observe functional improvements in the immune system when a patient, whose T-cells are low, is placed on HAART. His/her virus comes under control, T-cells rise, and on occasion a reactivation syndrome develops. A reactivation syndrome is when someone who had an opportunistic infection, but did not have the immune capacity to mount a significant attack prior to HAART, now possesses a capable immune attack. The patient is often made clinically ill by this improvement in immune function. Our ability to understand specific immune functions that may be either protective or detrimental remains under study.

Long Term Non-Progressors (LTNP):

These folks harbor immunological answers that will benefit the vast majority of individuals who in fact do have progressive HIV disease leading to AIDS. They can be defined as having HIV infection and an ability to control replication while experiencing no loss of immune cells or function. Many of these individuals show a genetic similarity, called HLA-B5701, which may offer a clue as to why they are able to suppress HIV. It doesn't appear that the frequency of HIV specific CD8+ T-cells in these individuals is correlated with their low viral loads. In fact when compared to individuals with greater viral loads, as a group, LTNP's possess less HIV specific CD8+ T-cells, but perhaps more highly focused responses. In other words, they may not have the amount of response that someone who is progressing with HIV disease has, but perhaps they possess the all important protective responses. One area where a correlation with protection has been documented is with a response to the virus' p24 protein. LTNP's when compared to non-LTNP's are able to make a response to p24. Interestingly, when individuals who were not LTNP's and were on various HAART regimens, took a break (STI) from their HAART, their responses to p24 plummetted. When those individuals restarted HAART, their p24 response as well as Gag specific response significantly improved. Thus perhaps the theory of interrupting HAART to prime a protective immune response is opposite of what actually happens when an individual stops HAART and allows HIV viremia to return.

Who Cares:

If one wants to treat, cure, or keep patients infected with HIV from getting ill, then there are two possibly focuses - the HIV virus or the human immune system. If one wants to stop the worldwide pandemic of HIV transmissions then there are two possibly focuses - the HIV virus or the human immune system.

Almost all of our advances in HIV medicine have been in the arena of attacking the virus directly with antiviral therapeutics. To date these products have given many patients longer and healthier lives, but they are not without their drawbacks. They must be taken frequently and religiously. They have side effects. No combination to date is able to eradicate infection. They are too costly to benefit most of the world's infected. Still, we shouldn't underestimate the amount of suffering that has been aleviated in the western world by these incredible antiviral products. And, if a safe and effective microbicide could be developed, attacking the virus will also prove to be valuable asset in the war on HIV transmission.

Focusing on the human immune system has even broader implications for the prevention and treatment of not only HIV but of many human infirmities: cancer, juevenile diabetes, and rheumatoid arthritis to name a few. A more complete understanding of the protective aspects of the immunity observed in LTNP's should allow us to recreate what those individuals naturally possess either with vaccine or gene therapy. Hopefully, benefiting both currently infected patients and allowing them to reduce or eliminate antiviral usage, while also offering the promise of preventing further spread of HIV.

- How important is the genetic makeup of your immune system? Specifically, how important is HLA subtypes, specifically B5701? Can we genetically modify immune systems adding this gene? Would that provide protection from AIDS?

- What about STI's? Is it too simplistic to think that simply interrupting therapy boosters HIV specific immunity?

- How important are neutralizing antibodies? Will a protective vaccine require an antibody response as well as a CTL/HTL response?

- Is it possible to create an antibody vaccine that while not eliminating HIV can reduce viremia to the level where HIV antivirals are not required to prevent progression to AIDS?

- Can a successful CTL/HTL vaccine be made that is enduring?

- What about viral reservoirs? If our HIV therapeutics become more potent with the advent of fusion inhibitors, chemokine inhibitors, and integrase inhibitors will we need to then think about long lived immune cells as our last hurdle to viral eradication? Can we discover new types of drugs that can empty viral reservoirs?

- What about local immunity? Could we develop a vaccine delivery system that would create a rectal, vaginal, and/or pharyngeal mucosa that fights HIV before it invades the systemic immune system?